Parathyroid hormone-related protein (PTHrP)
Structure
- PTHrP - gene PTHLH, chromosome 12 (PTH is chromosome 11)
- First 13 amino acids homologous to PTH -> binds the same PTH1 receptor
- -> identical downstream biochemistry, different biology
- A paracrine/autocrine developmental factor that behaves as a hormone only in disease
PTH vs PTHrP - the discriminator
| PTH | PTHrP | |
|---|---|---|
| Serum Ca | high | high |
| Serum PTH | high | suppressed |
| Phosphate | low | low |
| 1,25(OH)2D | high | low/normal |
| Bone | resorption + formation coupled | resorption uncoupled from formation |
| Urine Ca | variable | high |
- Both cause hypercalcaemia with hypophosphataemia. The suppressed PTH with a low 1,25(OH)2D is what makes it malignancy.
Epidemiology
- Humoral hypercalcaemia of malignancy = ~80% of malignancy-associated hypercalcaemia
- Hypercalcaemia affects ~2-3% of all cancer patients, up to 20-30% in some tumour types
- Commonest tumours: squamous cell (lung, head/neck, oesophagus, cervix), renal cell, breast, bladder, ovarian, HTLV-1 adult T-cell leukaemia/lymphoma
- Rare benign causes: massive lactating breast, benign phaeochromocytoma, mammary hyperplasia
Normal physiology
- Produced by nearly all fetal tissues; expression largely switches off after birth
- Roles:
- Placental calcium transport - drives maternal-to-fetal Ca gradient against the concentration gradient
- Endochondral bone development - with Indian hedgehog, a negative feedback loop keeping chondrocytes proliferating and delaying hypertrophic differentiation
- Mammary gland and tooth development, smooth muscle relaxation, skin/hair follicle
- Lactation: breast-derived PTHrP mobilises maternal skeletal calcium into milk
Loss and excess of signalling
- Loss of function (PTH1R or PTHrP) -> Blomstrand chondrodysplasia
- Lethal; premature chondrocyte differentiation -> advanced skeletal maturation, severely short limbs
- Gain of function (PTH1R) -> Jansen metaphyseal chondrodysplasia
- Short-limbed dwarfism + hypercalcaemia with undetectable PTH and PTHrP
In malignancy
- Tumour secretes PTHrP -> PTH1R in bone and kidney
- inc osteoclastic resorption via RANKL, dec osteoblastic formation (uncoupled)
- inc distal tubular Ca reabsorption
- dec proximal tubular PO4 reabsorption -> phosphaturia
- Fails to stimulate renal 1-alpha-hydroxylase as PTH does -> 1,25(OH)2D not raised
- Bone metastases are not required - HHM occurs with no skeletal disease at all
- Breast cancer: PTHrP also acts locally in bone metastases ("vicious cycle" with TGF-beta) - a separate mechanism from humoral hypercalcaemia
When to measure
- Hypercalcaemia with suppressed PTH and no obvious vitamin D or granulomatous cause
- Do not send PTHrP before PTH - PTH is the branch point
Interpretation
- Raised PTHrP + suppressed PTH -> humoral hypercalcaemia of malignancy
- -> look for occult squamous or renal primary if not known
- Normal PTHrP + suppressed PTH + hypercalcaemia -> osteolytic metastases, myeloma, 1,25(OH)2D-mediated (lymphoma, sarcoid), thyrotoxicosis, vitamin D/A toxicity
- Assay is send-away with a slow turnaround in most Australian labs - treat empirically while waiting
Supporting features
- Rapid onset, severe (often >3.5 mmol/L), symptomatic
- Metabolic alkalosis (vs the mild hyperchloraemic acidosis of PHPT)
- Markedly raised ALP if osteolytic metastases; normal in pure HHM
- Anaemia, weight loss, high ESR
Management of hypercalcaemia of malignancy
Treat the calcium, then treat the cancer. Antiresorptives fail if the tumour is not controlled.
- Saline rehydration 200-300 mL/hr, titrate to urine output
- Zoledronic acid 4 mg IV - the definitive step, onset 24-48 hr
- Denosumab 120 mg SC if bisphosphonate-refractory or eGFR <30 (no renal dose adjustment)
- Higher risk of prolonged, sometimes severe hypocalcaemia - check Ca at days 7 and 14
- Calcitonin for the first 48 hr only - tachyphylaxis
- Glucocorticoids do NOT work in PTHrP-mediated hypercalcaemia (they work in 1,25(OH)2D-mediated disease - lymphoma, sarcoid, vitamin D toxicity)
- Cease thiazides, calcium and vitamin D supplements
- Dialysis if refractory with renal failure
- Systemic anticancer therapy is the only durable control
- Anti-PTHrP antibodies remain experimental
- Recurrence within weeks is expected - a trigger for goals-of-care discussion, not just a repeat infusion
Associated tumours
- Squamous cell carcinoma - lung, head and neck, oesophagus, cervix, skin
- Renal cell carcinoma, transitional cell carcinoma
- Breast and ovarian carcinoma
- HTLV-1-associated adult T-cell leukaemia/lymphoma (PTHrP + RANKL)
- Neuroendocrine tumours, phaeochromocytoma, islet cell tumours
- Blomstrand chondrodysplasia (PTH1R/PTHrP loss of function)
- Jansen metaphyseal chondrodysplasia (PTH1R gain of function)
- Lactation and massive mammary hyperplasia (benign, transient)
Prognosis
- Median survival ~30 days once hypercalcaemia of malignancy develops
- Independent adverse prognostic marker across tumour types
- Responds to a first bisphosphonate in ~70-80%; response rate and duration fall with each recurrence
- Denosumab salvages many bisphosphonate-refractory cases
Complications
- AKI - volume depletion + nephrogenic DI
- Nephrocalcinosis, nephrolithiasis
- Arrhythmia, short QT, coma
- Osteonecrosis of the jaw, atypical femoral fracture with prolonged antiresorptive therapy
- Hypocalcaemia after denosumab - particularly in renal impairment or vitamin D deficiency; replete vitamin D first
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